The broad and long-term objective of this research project is to test the hypothesis that repetitive rapid activities (RRAs) within the thoracic veins underlie the mechanisms of sustained atrial fibrillation (AF). Recent studies show that paroxysmal AF episodes are often initiated and maintained by RRAs from the thoracic veins, including pulmonary veins, the vein of Marshall, and the superior vena cava. Sustained AF includes both persistent AF and permanent AF. While RRAs in the thoracic veins underlie the mechanisms of paroxysmal AF, the relation between RRAs and the mechanisms of sustained AF is less clear. The purpose of the present grant proposal is to perform studies in humans and in a canine model to test the Thoracic Vein Hypothesis of sustained AF. Specific Aims: (1) We will perform intraoperative mapping studies and radiofrequency (RF) ablation studies in human patients with sustained AF to demonstrate the presence of RRAs in human thoracic veins, and to compare the activation rate within the thoracic veins and those in the LA and RA. (2) Effects of sympathetic stimulation, beta blockade and antiarrhythmic drugs on a canine model of sustained AF induced by rapid pacing of the thoracic veins. We will perform chronic rapid pacing of the extrapericardial portion of a canine thoracic vein to induce sustained AF. High density computerized mapping will be used to determine whether or not there are RRAs from all thoracic veins. We will then determine if the RRAs can be suppressed or enhanced by pharmacological or electrophysiological intervention. (3) Thoracic veins in dogs can fibrillate without being connected to the atria. Using RF ablation technique, one of the thoracic veins will be electrically isolated at its junction from the remainder of the atria. Chronic rapid pacing will be performed from that vein to determine if sustained RRAs can be induced within the vein without being electrically connected to the atria. (4) Termination of sustained AF by thoracic vein isolation. We will induce AF by chronic rapid pacing in a thoracic vein. During second surgery, we will perform epicardial RF catheter ablation to electrically isolate all thoracic veins from the atria. (5) Immunocytochemical studies of the thoracic veins. We will use immunocytochemical staining techniques to determine if there are pacemaking cells in the thoracic veins, and whether or not the location of the pacemaking cells correlate with the sites of RRAs.